CN110974828B - Application of compound Axitinib in preparation of medicine for treating cerebrovascular diseases and pharmaceutical composition of compound Axitinib - Google Patents
Application of compound Axitinib in preparation of medicine for treating cerebrovascular diseases and pharmaceutical composition of compound Axitinib Download PDFInfo
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Abstract
The invention relates to the technical field of medicines, and discloses application of a compound Axitinib in preparation of medicines for treating cerebrovascular diseases and a pharmaceutical composition thereof, wherein the compound Axitinib is N-methyl-2- [3- ((E) -2-pyridine-2-yl-vinyl) -1H-indole-6-yl sulfonyl chloride]-benzamide, of formula (la). The technical scheme of the invention obviously reduces the cerebral infarction volume in the small acute stage of focal cerebral ischemia and obviously improves the neurological symptoms, has the cerebral neuroprotective effect, and particularly has cerebral ischemia protecting effectHas good effect on diseases.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to application of a compound Axitinib in preparing a medicine for treating cerebrovascular diseases and a pharmaceutical composition thereof.
Background
Cerebral apoplexy is a group of diseases which take ischemic brain tissue and hemorrhagic injury symptoms as main clinical manifestations, and is also called cerebral apoplexy or cerebrovascular accident. The disease is acute, has extremely high disability rate and fatality rate, is the second leading cause of death in the world at present, and becomes more serious with the aging of the population. The acute ischemic stroke (acute cerebral infarction) is the most common stroke type, and accounts for 69.6-70.8% of stroke in China, the fatality rate of a Chinese hospitalized acute ischemic stroke patient in 1 month is about 2.3-3.2%, the fatality rate in 3 months is 9-9.6%, the fatality/disability rate is 34.5-37.1%, the fatality rate in 1 year is 14.4-15.4%, and the fatality/disability rate is 33.4-33.8%, and the stroke type is the first cause of fatality/disability in China.
The pathogenesis of ischemic stroke is complex, and relates to various mechanisms such as peroxidation, energy metabolism disorder, calcium overload, excitatory amino acid toxicity and the like. The only drug currently approved by the FDA for the treatment of ischemic cerebral stroke in the united states is tissue-type plasminogen activator (t-PA), which dissolves thrombi, recanalizes blood vessels, and restores blood flow. However, only a small fraction of patients receive thrombolytic therapy due to the narrow therapeutic window of t-PA (effective 4.5 hours post-stroke) and the propensity to cause bleeding. Therefore, the problem of searching a new target for treating ischemic cerebral apoplexy and a medicine with a new action mechanism and less adverse reactions is urgently needed to be solved.
Disclosure of Invention
The invention aims to overcome the problems in the existing medicaments for treating cerebrovascular diseases, and provides application of a compound Axitinib in preparing medicaments for treating cerebrovascular diseases and a medicinal composition thereof, wherein the compound Axitinib has obvious cerebral nerve protection effect, can obviously reduce the cerebral infarction volume of a rat with focal cerebral ischemia in the acute stage and obviously improve the neurological symptoms of the rat with the focal cerebral ischemia, and can be used for preventing or treating ischemic brain injury, cerebral thrombosis, cerebral embolism, cerebral infarction, cerebral apoplexy, lacunar infarction, transient cerebral ischemia, cerebral arteriosclerosis, diabetic cerebrovascular complications and other diseases.
In order to achieve the above object, the present invention provides a use of Axitinib in a first aspect of the invention for the preparation of a medicament for the treatment of cerebrovascular diseases, said compound Axitinib being N-methyl-2- [3- ((E) -2-pyridin-2-yl-vinyl) -1H-indol-6-ylsulfonyl ] -benzamide, having the formula:
preferably, the cerebrovascular disease is ischemic brain injury disease.
Preferably, the ischemic brain injury disease includes cerebral stroke, cerebral thrombosis, cerebral embolism, cerebral infarction, transient cerebral ischemia, lacunar cerebral infarction, cerebral arteriosclerosis and diabetic cerebrovascular complications.
In a second aspect, the present invention provides a pharmaceutical composition for treating cerebrovascular diseases, which is characterized by comprising a compound Axitinib and a pharmaceutically acceptable carrier and/or adjuvant, wherein the compound Axitinib is N-methyl-2- [3- ((E) -2-pyridin-2-yl-vinyl) -1H-indol-6-ylsulfonyl ] -benzamide, and the structural formula thereof is:
preferably, the pharmaceutical composition is a solvent or diluent.
Preferably, the pharmaceutical composition is a formulation suitable for oral, rectal, topical, buccal, sublingual, subcutaneous, intramuscular, intravenous.
Preferably, the pharmaceutical composition is a tablet, capsule, dispersible powder or granule.
Preferably, the pharmaceutical composition is an injectable formulation.
By adopting the technical scheme, the cerebral infarction volume in the small acute stage of the focal cerebral ischemia can be obviously reduced, the neurological symptoms can be obviously improved, the cerebral nerve protective effect is achieved, and particularly, the cerebral ischemic disease has a good effect. The prepared medicine can be used for treating ischemic brain injury, cerebral thrombosis, cerebral embolism, cerebral infarction, cerebral apoplexy, lacunar cerebral infarction, transient cerebral ischemia, cerebral arteriosclerosis, diabetic cerebrovascular complications and other diseases.
Drawings
FIG. 1 is a schematic representation of the effect of the compound Axitinib of example 1 of the present invention on the improvement of neurological symptoms in mice with cerebral ischemia;
FIG. 2 is a graph showing the effect of the compound Axitinib of example 1 on the improvement of the grip test in mice with cerebral ischemia;
FIG. 3 is a graph showing the effect of Axitinib compound in example 1 on improving the right limb usage in mice with cerebral ischemia;
FIGS. 4a and 4b are graphs showing the effect of the compound Axitinib of example 1 in reducing the volume of cerebral infarction in the acute phase of mice with cerebral ischemia.
Detailed Description
The following describes the embodiments of the present invention in detail. It should be understood that the detailed description and specific examples, while indicating the present invention, are given by way of illustration and explanation only, not limitation.
The present invention will be described in detail below by way of examples. In the following examples, each material used was commercially available unless otherwise specified, and the method used was a conventional method in the art unless otherwise specified.
Axitinib is an oral small molecule tyrosine kinase inhibitor that selectively inhibits the activity of VEGFR-1,2,3, PDGFR and c-Kit, and is approved by the FDA in us for the treatment of advanced kidney cancer (renal cell carcinoma) by Axitinib (trade name, inlyta) from feverfew on day 27/1/2012. The inventor of the invention researches and finds that: after cerebral ischemia occurs, levels of VEGFD increase in brain tissue and ischemic astrocytes. VEGFD has VEGFR2/VEGFR3 as the main action target, so that small dose of Axitinib can be found to treat ischemic cerebral apoplexy, thereby completing the invention.
In a first aspect, the present invention provides an application of a compound Axitinib in preparing a medicament for treating cerebrovascular diseases, wherein the compound Axitinib is N-methyl-2- [3- ((E) -2-pyridin-2-yl-vinyl) -1H-indol-6-ylsulfonyl ] -benzamide, and the structural formula of the compound is:
in the present invention, preferably, the cerebrovascular disease is ischemic brain injury disease.
The above ischemic brain injury diseases are not particularly limited and include, but are not limited to, cerebral stroke, cerebral thrombosis, cerebral embolism, cerebral infarction, transient cerebral ischemia, lacunar infarction, cerebral arteriosclerosis and diabetic cerebrovascular complications, and in the present invention, it is preferable that the ischemic brain injury diseases include cerebral stroke, cerebral thrombosis, cerebral embolism, cerebral infarction, transient cerebral ischemia, lacunar infarction, cerebral arteriosclerosis and diabetic cerebrovascular complications.
In a second aspect, the present invention provides a pharmaceutical composition for treating cerebrovascular diseases, which comprises a compound Axitinib and a pharmaceutically acceptable carrier and/or adjuvant, wherein the compound Axitinib is N-methyl-2- [3- ((E) -2-pyridin-2-yl-vinyl) -1H-indol-6-ylsulfonyl ] -benzamide, and has a structural formula of:
in the present invention, there is no particular limitation on the type of formulation of the pharmaceutical composition, and may be a formulation including those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and articular), rectal and topical (including dermal, buccal, sublingual and intraocular) administration. In the present invention, the pharmaceutical composition is a solvent or diluent.
In the present invention, preferably, the pharmaceutical composition is a formulation suitable for oral, rectal, topical, buccal, sublingual, subcutaneous, intramuscular, intravenous. The most suitable route may depend on the condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.
Possible forms of presentation for the above-mentioned formulations suitable for oral administration are in the form of discrete units, which may be, for example, capsules or tablets, powders or granules, solutions or suspensions of aqueous or non-aqueous liquids, or oil-in-water or water-in-oil emulsions, containing a predetermined amount of the active ingredient. The active ingredient may also be present in the form of a pill or paste. In the present invention, preferably, the pharmaceutical composition is a tablet, a capsule, a dispersible powder or a granule.
The tablets may be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable apparatus the active ingredient in a free-flowing form, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable apparatus the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated to provide sustained, delayed or controlled release of the active ingredient.
For the above formulations for parenteral administration, aqueous and non-aqueous sterile injection solutions containing antioxidants, buffers, bacteriostats and solutes are included. Formulations for parenteral administration also include aqueous and non-aqueous sterile suspensions, which may contain suspending agents and thickening agents.
In the present invention, preferably, the pharmaceutical composition is in the form of an injectable preparation.
The various dosage forms for the above-described pharmaceutical compositions of the present invention may be prepared according to methods well known in the pharmaceutical art.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.
The invention is further described below with reference to the following figures and examples:
example 1
Protection of mouse focal ischemic cerebral stroke by Axitinib.
Male C57 mice were randomly divided into a control group (sham), a model group, and an Axitinib administration group (30 pmol/kg, 60nmol/kg, 120 nmol/kg), each of which contained 10 mice. A mouse transient middle cerebral artery occlusion model (tMCAO) was made using the wire-embolus method. Reperfusion was performed after 90min of ischemia, and different concentrations of Axitinib were intraperitoneally injected 12 hours after reperfusion. The mouse is cut off and the brain is taken out and sliced to observe the influence of the Axitinib on the cerebral infarction volume in the acute stage of cerebral ischemia. Mice after reperfusion (I/R) were scored for neurological symptoms during acute phase of cerebral ischemia using Longa method before sacrifice, with higher scores being more pronounced for neurological deficits. And measuring the mouse grip and observing the mouse right limb usage rate by a barrel experiment to evaluate the improvement of the mouse neurological symptoms. The neurological symptom scoring criteria are shown in table 1.
TABLE 1
| Scoring | |
| 0 | Normal, no impairment of neural function |
| 1 | Incomplete extension of the left forelimb and mild impairment of the |
| 2 | Lateral paralysis of the rat during walking and moderate nerve function damage |
| 3 | When the rat walks, the rat topples to the paralyzed side and seriously damages the nerve function |
| 4 | The rat can not walk at all and the consciousness is disturbed |
FIG. 1 is a schematic representation of the effect of the compound Axitinib of example 1 of the present invention on the improvement of neurological symptoms in mice with cerebral ischemia; mean ± SD, n =10; in comparison with the set of models, ** p<0.01. as can be seen from fig. 1: the compound Axitinib was able to reduce neurological symptom scores in mice with cerebral ischemia.
FIGS. 4a and 4b are graphs showing the effect of the compound Axitinib of example 1 in reducing the volume of cerebral infarction in the acute phase of mice with cerebral ischemia; mean ± SD, n =10; in comparison with the set of models, * p<0.05， ** p<0.01. as can be seen from fig. 4a and 4 b: the compound Axitinib can reduce the cerebral infarction volume of an acute stage of a cerebral ischemic mouse.
Barrel experiment: the mice were placed in the drums and observed for use with their forelimbs touching the walls of the drums. After the forelimb of the mouse is put down from the barrel wall, the condition that the lower left limb and the lower right limb are attached to the barrel wall is recorded. This was done 10 times per mouse. The final statistical formula is (number of non-impaired forelimb movements-number of impaired forelimb movements)/(number of non-impaired forelimb movements + number of forelimb joint movements).
And measuring the mouse grip and observing the mouse right limb usage rate by a barrel experiment to evaluate the improvement of the mouse neurological symptoms.
FIG. 2 shows the present inventionA schematic diagram illustrating the effect of the compound Axitinib of example 1 on the grip test of mice with improved cerebral ischemia; mean ± SD, n =10; in comparison with the set of models, ** p<0.01. as can be seen from fig. 2: the compound Axitinib can improve the holding power of cerebral ischemia mice.
FIG. 3 is a graph showing the effect of Axitinib, a compound of example 1, on improving right limb usage in mice with cerebral ischemia; mean ± SD, n =10; in comparison with the set of models, * p<0.05. as can be seen from fig. 3: the compound Axitinib can improve the right limb usage rate of cerebral ischemia mice.
The above results show that: axitinib has a certain protective effect on ischemic brain injury, and can be used for preventing and treating the diseases.
The preferred embodiments of the present invention have been described above in detail, but the present invention is not limited thereto. Within the scope of the technical idea of the invention, many simple modifications can be made to the technical solution of the invention, including combinations of various technical features in any other suitable way, and these simple modifications and combinations should also be regarded as the disclosure of the invention, and all fall within the scope of the invention.
Claims (1)
1. The application of a compound Axitinib in preparing a medicament for treating ischemic cerebral apoplexy, wherein the compound Axitinib is N-methyl-2- [3- ((E) -2-pyridin-2-yl-vinyl) -1H-indol-6-ylsulfonyl ] -benzamide, and the structural formula is as follows:
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| CN113209097A (en) * | 2021-06-04 | 2021-08-06 | 浙江大学 | Application of axitinib and analogue in preparation of medicine for resisting cerebral arterial thrombosis |
| WO2024003380A1 (en) * | 2022-06-30 | 2024-01-04 | Icm (Institut Du Cerveau Et De La Moelle Épinière) | Vascular endothelial growth factor receptor-1 (vegfr-1) inhibitors for promoting myelination and neuroprotection |
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